Incidence and prevalence of musculoskeletal health conditions in survivors of childhood and adolescent cancers: A report from the Swiss childhood cancer survivor study.

PURPOSE: Childhood cancer and its treatment can cause damage to the musculoskeletal system. We aimed to determine the incidence and prevalence of musculoskeletal health conditions (MSHC) in survivors, and to investigate differences by cancer-related characteristics. METHODS: We used data from the Childhood Cancer Registry and the Swiss Childhood Cancer Survivor Study, including survivors (≥5 years since diagnosis; diagnosed 1976-2015 at <20 years of age) aged ≥15 years at study. Cumulative incidence and prevalence of MSHCs (osteoporosis, limb length discrepancy, limited joint mobility, bone/joint pain, scoliosis, changes to chest/ribs and amputation) were calculated from self-reported data. RESULTS: We included 2645 survivors (53% men; median age 24 years, range 15-59 years). Prevalence and cumulative incidence of any MSHC was 21% and 26%, respectively. Incidence rate for any MSHC was 15.6/1000 person-years. Scoliosis (8%), bone/joint pain (7%) and limited joint mobility (7%) were the most prevalent MSHC. MSHC co-occurred with other health conditions in 87% of survivors. We found increased rates of MSHC in women (RR = 1.4, 95%CI: 1.2-1.7), bone tumour survivors (RR = 6.0, 95%CI: 4.5-7.9), survivors older at diagnosis (11-15 years: RR = 1.8, 95%CI: 1.5-2.3), after a relapse (RR = 1.5, 95%CI: 1.3-1.9), treatment with surgery (RR = 1.2, 95%CI: 1.0-1.5), chemotherapy (RR = 1.4, 95%CI: 1.1-1.8) or stem cell transplantation (RR = 1.6, 95%CI: 1.0-2.5), and more recent year of diagnosis (2011-2015: RR = 4.3, 95%CI: 2.8-6.8). CONCLUSION: MSHCs are prevalent in survivors, the risk is increasing in younger survivor cohorts, and MSHCs usually occur in multimorbid survivors. Strengthening of rehabilitation services and appropriate referrals are needed to mitigate the effects of the cancer and cancer treatment.

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development.

BACKGROUND: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. METHODS: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. FINDINGS: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. INTERPRETATION: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. FUNDING: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

Auditory complications among childhood cancer survivors and health-related quality of life: a PanCareLIFE study.

PURPOSE: Auditory complications are potential side effects from childhood cancer treatment. Yet, limited evidence exists about the impact of auditory complications-particularly tinnitus-on health-related quality of life (HRQoL) among childhood cancer survivors (CCS). We determined the prevalence of hearing loss and tinnitus in the European PanCareLIFE cohort of CCS and examined its effect on HRQoL. METHODS: We included CCS from four European countries who were diagnosed at age ≤ 18 years; survived ≥ 5 years; and aged 25-44 years at study. We assessed HRQoL (Short Form 36), hearing loss, and tinnitus using questionnaires. We used multivariable linear regression to examine associations between these two auditory complications and HRQoL adjusting for socio-demographic and clinical factors. RESULTS: Our study population consisted of 6,318 CCS (53% female; median age at cancer diagnosis 9 years interquartile range [IQR] 5-13 years) with median age at survey of 31 years (IQR 28-35 years). Prevalence was 7.5% (476/6,318; confidence interval [CI]: 6.9-8.2) for hearing loss and 7.6% (127/1,668; CI: 6.4-9.0) for tinnitus. CCS with hearing loss had impaired physical (coefficient [coef.] -4.3, CI: -7.0 to -1.6) and mental (coef. -3.2, CI: -5.5 to -0.8) HRQoL when compared with CCS with normal hearing. Tinnitus was associated with impaired physical (coef. -8.2, CI: -11.8 to -4.7) and mental (coef. -5.9, CI: -8.8 to -3.1) HRQoL. CONCLUSION: We observed reduced HRQoL among CCS with hearing loss and tinnitus. Our findings indicate timely treatment of hearing loss and tinnitus may contribute to quality of life of survivors. IMPLICATIONS FOR CANCER SURVIVORS: CCS who experience auditory complications should be counseled about possible therapeutic and supportive measures during follow-up care.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Health behaviour of women with Turner Syndrome.

AIM: This study assessed lifestyle-related risk factors for cardiovascular disease in young women with Turner syndrome. METHODS: In 2012, we sent a questionnaire to women with Turner syndrome aged ≥18 years and living in Switzerland with questions on socio-demographic and medical data as well as health behaviour. We compared the reported lifestyle with that of women from the Swiss Health Survey 2012, a representative survey of the general population. RESULTS: Fifty-seven per cent (45/79) of women with Turner syndrome answered the questionnaire (mean age: 24 years). Eighty per cent (36/45) had never smoked compared with 58% (1156/1972) of the general population (p < 0.01). Women with Turner syndrome engaged less often in binge drinking (34% vs. 71%) (p < 0.001), but consumed alcohol equally often as the general population (p = 0.327). They performed sports as often as the general population (p = 0.34), but only one quarter (11/45) of women with Turner syndrome adhered to official physical activity recommendations. CONCLUSION: Although most women with Turner syndrome had a healthy lifestyle, only a minority had sufficient physical activity. Paediatricians should promote structured physical activity in girls with Turner syndrome from early childhood onwards to reduce their cardiovascular risk in adulthood and to increase long-term health-related quality of life.

Health-Related Quality of Life in European Childhood Cancer Survivors: Protocol for a Study Within PanCareLIFE.

BACKGROUND: Survival after childhood cancer has improved to more than 80% during the last few years, leading to an increased number of childhood cancer survivors. Cancer itself, or its treatment, may cause chronic health conditions, including somatic and mental sequelae, which may affect survivors' health-related quality of life (HRQoL). OBJECTIVE: The project PanCareLIFE aims to establish a large database with comprehensive data on childhood cancer survivors from different European countries, including data on HRQoL. Within PanCareLIFE, this study aims to describe HRQoL in survivors, investigate predictors of HRQoL, and describe the association of HRQoL with hearing and female fertility impairment. This paper describes the design of the HRQoL study, the origin of data, strategies for data collection, and sampling characteristics of survivors from each contributing country. METHODS: A total of 6 institutions from 5 European countries (the Czech Republic, France, Germany, the Netherlands, and Switzerland) provided data on HRQoL assessed with the Short Form 36 and on relevant predictors. The central PanCareLIFE data center aggregated the data and harmonized the variables between the institutions. Survivors were eligible if they received a diagnosis of cancer according to the 12 main groups of the International Classification of Childhood Cancer, 3rd edition, or Langerhans cell histiocytosis; were aged ≤18 years at the time of diagnosis; were residents of the respective country at the time of diagnosis; had survived ≥5 years after cancer diagnosis; were aged ≥18 years at the time of the questionnaire survey; and did not refuse to registration in the national or local childhood cancer cohort. RESULTS: We identified 24,993 eligible survivors. Of those, 19,268 survivors received a questionnaire and 9871 survivors participated, resulting in response rates of 9871/24,993 (39.50%) of eligible survivors and of 9871/19,268 (51.23%) invited survivors. Most participants were diagnosed with cancer between the ages of 10 and 14 years (3448/9871, 34.93%) or <5 years (3201/9871, 32.43%). The median age was 8 years. Of the 9871 participants, 3157 (31.97%) were survivors of leukemia, 2075 (21.02%) lymphoma, and 1356 (13.7%) central nervous system (CNS) tumors. Most participants (9225/9871, 93.46%) had no history of a subsequent tumor; 77.45% (7645/9871) received chemotherapy with or without other treatments. More than half (5460/9871, 55.31%) were aged 25 to 34 years at the time of the HRQoL study. Participating survivors differed from nonparticipants; participants were more often women, survivors of leukemia or lymphoma, and less frequently, survivors of CNS tumors than nonparticipants. CONCLUSIONS: PanCareLIFE successfully assessed HRQoL and its predictors in 9871 European survivors of childhood cancer. This large population will permit detailed investigations of HRQoL after childhood cancer, particularly the impact of hearing and female fertility impairment on HRQoL. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/21851.

Premature Adrenarche in Girls Characterized By Enhanced 17,20-Lyase and 17ß-Hydroxysteroid Dehydrogenase Activities.

CONTEXT: Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche is unknown and the role of novel biosynthetic pathways remains unclear. OBJECTIVE: To compare the urinary steroid metabolome and enzyme activities of girls with PA to age-matched control girls and to published steroid values of girls with normal adrenarche and of women with PCOS and their newborn daughters. DESIGN: Prospective observational study from 2009 to 2014. SETTING: Academic pediatric endocrinology referral center. PARTICIPANTS: Twenty-three girls with PA and 22 healthy, age-matched girls. MAIN OUTCOME MEASURES: Steroid metabolites in 24-hour urine samples, including 4 progesterones, 5 corticosterones, aldosterone, 13 androgens, 2 estrogens, 14 glucocorticoids, and enzyme activities represented by metabolite ratios. RESULTS: Girls with PA had a higher body mass index (mean standard deviation scores 0.9 vs -0.3, P = 0.013). Androgen excretion was higher in PA girls than in control girls (median 3257 nmol/24 hours vs 1627 nmol/24 hours, P < 0.001), in particular metabolites from alternate androgen pathways. The amount of progesterone, corticosterone, aldosterone, estrogen, and cortisol metabolites were similar between groups. Activities of 17ß-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3ß-hydroxysteroid-dehydrogenase, 21-hydroxylase, and 5α-reductase activity were not different between groups, in contrast to published results on girls with normal adrenarche or PCOS females. CONCLUSIONS: Metabolites and enzymes involved in alternate androgen pathways appear to be markers of PA. Prospective studies should assess whether steroid production in PA also differs from adrenarche at normal timing and persists into adulthood.

Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014.

BACKGROUND: Incidence of childhood cancer increased in most countries worldwide, but reasons are unclear. This study investigates trends of childhood cancer incidence in Switzerland from 1985 to 2014. METHODS: We extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends of annual age-standardised incidence using JoinPoint regression models. RESULTS: Over the study period from 1985 to 2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p < 0.001). Using the World standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Incidence increased by 0.7% (95% confidence interval (CI) 0.5; 1.0) per year for all cancers from 1985 to 2014, 0.8% (95% CI 0.2%-1.4%) for leukaemias over the same period, 3.0% (95% CI 0.2%-1.4%) for CNS tumours during 1985-2002, and 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas over the period 1985-2014. CONCLUSION: Trends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and due to risk factors that experience similar increases in trends.

Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort.

Context: There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. Objective: To examine meningioma risks in relation to GH treatment. Design: Cohort study with follow-up via cancer registries and other registers. Setting: Population-based. Patients: A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Main Outcome Measures: Risk of meningioma incidence. Results: During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. Conclusions: Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy.

Hearing loss and quality of life in survivors of paediatric CNS tumours and other cancers.

PURPOSE: Hearing loss, a complication of cancer treatment, may reduce health-related quality of life (HRQoL), especially in childhood cancer survivors of central nervous system (CNS) tumours who often have multiple late effects. We examined the effect of hearing loss on HRQoL in young survivors of CNS and other childhood cancers. METHODS: Within the Swiss Childhood Cancer Survivor Study, we sent questionnaires about hearing loss and HRQoL (KIDSCREEN-27) to parents of survivors aged 8-15 years. We stratified the effect of hearing loss on HRQoL by cancer diagnosis, using multivariable logistic regression and adjusting for sociodemographic and clinical factors. RESULTS: Hearing loss was associated with impaired physical well-being [unadjusted estimated differences - 4.6 (CI - 9.2, - 0.1); adjusted - 4.0 (CI - 7.6, - 0.3)] and peers and social support [unadjusted - 6.7 (CI - 13.0, - 0.3); adjusted - 5.0 (CI - 10.5, 0.9)] scores in survivors of CNS tumours (n = 123), but not in children diagnosed with other cancers (all p-values > 0.20, n = 577). CONCLUSION: Clinicians should be alert to signs of reduced physical well-being and impaired relationships with peers. Especially survivors of CNS tumours may benefit most from strict audiological monitoring and timely intervention to mitigate secondary consequences of hearing loss on HRQoL.

Monitoring pulmonary health in Swiss childhood cancer survivors.

BACKGROUND: Childhood cancer survivors are at increased risk for pulmonary morbidity and mortality. International guidelines recommend pulmonary function tests (PFT) during follow-up care. This nationwide study assessed how many children received PFT within 5 years after pulmotoxic treatment in Switzerland, types of tests, and predictors for testing. METHODS: We included all children from the Swiss Childhood Cancer Registry who were diagnosed with cancer from 1990 to 2013 at age 0-16 years, survived for ≥2 years from diagnosis, and had pulmotoxic chemotherapy with bleomycin, busulfan, nitrosoureas, and/or chest radiotherapy. We searched medical records in all Swiss pediatric oncology clinics for PFT (spirometry, plethysmography, diffusion capacity of carbon monoxide [DLCO]) and treatment details. RESULTS: We found medical records for 372 children, of whom 147 had pulmotoxic chemotherapy and 323 chest radiotherapy. Only 185 had plethysmography and/or spirometry (50%), 122 had DLCO (33%). Testing varied by cancer center from 3% to 79% (P = 0.001). Central nervous system tumor survivors and those not treated according to study protocols had less plethysmography and/or spirometry (odds ratio (OR) 0.3 and 0.3), lymphoma survivors and those who were symptomatic had more PFT (plethysmography and/or spirometry: OR 5.9 and 8.7; DLCO: OR 3.4 and 2.3). Cumulative incidence (CuI) of PFT was 52% in the first 5 years after pulmotoxic treatment; most of the tests were done in the first 2 years after treatment (CuI 44%). CONCLUSION: Only half of the survivors exposed to pulmotoxic treatment have been followed up with PFT in Switzerland. We need to optimize, update, and implement monitoring guidelines.

Long-term pulmonary disease among Swiss childhood cancer survivors.

BACKGROUND: Pulmonary diseases are potentially severe late complications of childhood cancer treatment that increase mortality risk among survivors. This nationwide study assesses the prevalence and incidence of pulmonary diseases in long-term childhood cancer survivors (CCS) and their siblings, and quantifies treatment-related risks. METHODS: As part of the Swiss Childhood Cancer Survivor Study, we studied CCS who were diagnosed between 1976 and 2005 and alive at least 5 years after diagnosis. We compared prevalence of self-reported pulmonary diseases (pneumonia, chest wall abnormalities, lung fibrosis, emphysema) between CCS and their siblings, calculated cumulative incidence of pulmonary diseases using the Kaplan-Meier method, and determined risk factors using multivariable logistic regression. RESULTS: CCS reported more pneumonias (10% vs. 7%, P = 0.020) and chest wall abnormalities (2% vs. 0.4%, P = 0.003) than siblings. Treatment with busulfan was associated with prevalence of pneumonia (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.1-14.9), and thoracic surgery was associated with chest wall abnormalities and lung fibrosis (OR 4.1, 95% CI 1.6-10.7 and OR 6.3, 95% CI 1.7-26.6). Cumulative incidence of any pulmonary disease after 35 years of follow-up was 21%. For pneumonia, the highest cumulative incidence was seen in CCS treated with both pulmotoxic chemotherapy and radiotherapy to the thorax (23%). CONCLUSION: This nationwide study in CCS found an increased risk for pulmonary diseases, especially pneumonia, while still young, which indicates that CCS need long-term pulmonary follow-up.

Low adherence to dietary recommendations in adult childhood cancer survivors.

BACKGROUND & AIMS: Poor diet may increase the risk that childhood cancer survivors (CCS) will suffer from chronic disease. We compared adherence to national dietary recommendations between CCS, their siblings and the Swiss population, identified determinants of adherence, and assessed the association of adherence with cardiovascular disease (CVD) risk profiles. METHODS: As part of the Swiss Childhood Cancer Survivor Study (SCCSS), a questionnaire was sent to all Swiss resident CCS aged <21 years at diagnosis, who survived ≥5 years and were 16-45 years old at the time of the survey. We compared dietary adherence between CCS, their siblings and participants in the Swiss Health Survey (SHS), a representative survey of the general population. A multivariable logistic regression was used to assess characteristics associated with dietary adherence. We sorted CCS into four kinds of CVD risk groups based on type of treatment (anthracyclines, chest irradiation, a combination, or neither). RESULTS: We included 1864 CCS, 698 siblings and 8258 participants of the general population. Only 43% of the CCS met the recommended dietary intakes for meat, 34% for fruit, 30% for fish, 18% for dairy products, 11% for vegetables, and 7% for combined fruit and vegetables. Results were similar for both control groups. In all groups, dietary adherence was associated with gender, parental education, migration background, language region in Switzerland, smoking, alcohol consumption and sport participation. CCS with a higher CVD risk profile because of cardiotoxic treatment had no better adherence. CONCLUSIONS: CCS have similar food patterns as their siblings and the general population, and poorly adhere to current recommendations. Awareness of the importance of a healthy diet should be raised among CCS, to prevent chronic diseases like CVD.

Validation of questionnaire-reported hearing with medical records: A report from the Swiss Childhood Cancer Survivor Study.

BACKGROUND: Hearing loss is a potential late effect after childhood cancer. Questionnaires are often used to assess hearing in large cohorts of childhood cancer survivors and it is important to know if they can provide valid measures of hearing loss. We therefore assessed agreement and validity of questionnaire-reported hearing in childhood cancer survivors using medical records as reference. PROCEDURE: In this validation study, we studied 361 survivors of childhood cancer from the Swiss Childhood Cancer Survivor Study (SCCSS) who had been diagnosed after 1989 and had been exposed to ototoxic cancer treatment. Questionnaire-reported hearing was compared to the information in medical records. Hearing loss was defined as ≥ grade 1 according to the SIOP Boston Ototoxicity Scale. We assessed agreement and validity of questionnaire-reported hearing overall and stratified by questionnaire respondents (survivor or parent), sociodemographic characteristics, time between follow-up and questionnaire and severity of hearing loss. RESULTS: Questionnaire reports agreed with medical records in 85% of respondents (kappa 0.62), normal hearing was correctly assessed in 92% of those with normal hearing (n = 249), and hearing loss was correctly assessed in 69% of those with hearing loss (n = 112). Sensitivity of the questionnaires was 92%, 74%, and 39% for assessment of severe, moderate and mild bilateral hearing loss; and 50%, 33% and 10% for severe, moderate and mild unilateral hearing loss, respectively. Results did not differ by sociodemographic characteristics of the respondents, and survivor- and parent-reports were equally valid. CONCLUSIONS: Questionnaires are a useful tool to assess hearing in large cohorts of childhood cancer survivors, but underestimate mild and unilateral hearing loss. Further research should investigate whether the addition of questions with higher sensitivity for mild degrees of hearing loss could improve the results.

Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited. Objective: To examine cancer risks in relation to GH treatment. Design: Cohort study. Setting: Population-based. Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics. Main Outcome Measures: Cancer incidence and cancer mortality. Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer). Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.

Long-term auditory complications after childhood cancer: A report from the Swiss Childhood Cancer Survivor Study.

BACKGROUND: Auditory complications are an adverse event of childhood cancer treatment, especially common in children treated with platinum chemotherapy or cranial radiation. Variation between diagnostic childhood cancer groups has rarely been studied, and we do not know if the burden of auditory complications has changed over the last decades. PROCEDURE: Within the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to all survivors who were diagnosed at age 16 years or less between 1976 and 2005. We compared prevalence of self-reported hearing loss and tinnitus between all diagnostic childhood cancer groups and siblings, used multivariable logistic regression to analyze the effect of treatment-related factors on hearing loss, and compared the cumulative incidence of hearing loss between different periods of cancer diagnosis. RESULTS: Prevalence of self-reported hearing loss was higher in survivors (10%) than in siblings (3%, P < 0.001), and highest in survivors of central nervous system tumors (25%). Significant risk factors were treatment with platinum compounds (carboplatin: odds ratio [OR] 2.4; cisplatin: OR 9.4), cranial radiation (>29 Gy: OR >1.7), or brain surgery (OR 2.2). Children diagnosed in 1986-1995, when platinum compounds came into widespread use, had a significantly higher cumulative incidence of hearing loss than those diagnosed in 1976-1985. In the most recent period, 1996-2005, the risk decreased again, both for patients treated with platinum compounds and with cranial radiation. CONCLUSIONS: Our data show that the burden of hearing loss has stabilized in recently treated survivors, suggesting that survivors have benefited from new treatment regimens that use less ototoxic radiation and more carefully dosed platinum compounds.

Income in Adult Survivors of Childhood Cancer.

INTRODUCTION: Little is known about the impact of childhood cancer on the personal income of survivors. We compared income between survivors and siblings, and determined factors associated with income. METHODS: As part of the Swiss Childhood Cancer Survivor Study (SCCSS), a questionnaire was sent to survivors, aged ≥18 years, registered in the Swiss Childhood Cancer Registry (SCCR), diagnosed at age <21 years, who had survived ≥5 years after diagnosis of the primary tumor. Siblings were used as a comparison group. We asked questions about education, profession and income and retrieved clinical data from the SCCR. We used multivariable logistic regression to identify characteristics associated with income. RESULTS: We analyzed data from 1'506 survivors and 598 siblings. Survivors were less likely than siblings to have a high monthly income (>4'500 CHF), even after we adjusted for socio-demographic and educational factors (OR = 0.46, p<0.001). Older age, male sex, personal and parental education, and number of working hours were associated with high income. Survivors of leukemia (OR = 0.40, p<0.001), lymphoma (OR = 0.63, p = 0.040), CNS tumors (OR = 0.22, p<0.001), bone tumors (OR = 0.24, p = 0.003) had a lower income than siblings. Survivors who had cranial irradiation, had a lower income than survivors who had no cranial irradiation (OR = 0.48, p = 0.006). DISCUSSION: Even after adjusting for socio-demographic characteristics, education and working hours, survivors of various diagnostic groups have lower incomes than siblings. Further research needs to identify the underlying causes.